DESCRIPTION (provided by investigator): Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the United States. Smoking is the principal cause of COPD but only a minority of smokers develops symptomatic COPD. Therapeutic options for COPD are limited;in part due to a limited understand of COPD pathogenesis. Pulmonary vascular changes are generally though to occur late in COPD, secondary to severe hypoxemia. Recent bench research, however, has shown endothelial cell dysfunction and vascular endothelial growth factor (VEGF)-mediated apoptosis in early COPD. These observations have revived the vascular hypothesis of COPD, which posits that alterations in the pulmonary vasculature lead to loss of lung function. We found impaired endothelial function and reduced cardiac output with preserved LV function in early COPD among smokers in two cohort studies, the EMCAP Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. These findings suggest that endothelial dysfunction and pulmonary vascular changes occur in early COPD. The proposed study is a cross-sectional study of smokers nested among the two cohorts, which together provide a well-defined sampling frame of 4,617 participants with prior spirometry and CT measures. A total of 325 participants (100 cases with mild, 75 cases with moderate, and 50 cases with severe COPD, and 100 healthy controls) will be characterized with MR and full-lung CT imaging, spirometry, flow cytometry, and gene expression profiling to test the following hypotheses: 1) Functional and structural changes in the pulmonary vasculature and right ventricle occur early in COPD;2) Endothelial microparticles, circulating endothelial cells, and endothelial progenitor cells are abnormal early in COPD;3) Plasma VEGF levels and gene expression of apoptotic and nitrogen oxide metabolism pathways in peripheral blood mononucleated cells (PBMCs) are altered early in COPD. Innovative aspects of this application include novel imaging modalities, flow cytometry assays of endothelial health, and mRNA expression in PBMCs to test a potentially paradigm-shifting hypothesis. Confirmation of the vascular hypothesis of COPD would justify testing existing (e.g., statins) and novel (e.g., stem cell) therapies targeted to endothelial dysfunction in COPD. PUBLIC HEALTH RELEVANCE Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of death in the United States. COPD will overtake stroke as the third leading cause of death in 10-15 years. Therapeutic options for COPD are few;in part due to a limited understand of COPD pathogenesis. This study is designed to test a novel hypothesis of endothelial dysfunction and pulmonary hypertension early in the pathogenesis of COPD. If confirmed, this hypothesis would lead to the testing of currently available (e.g., statins) and novel (e.g., stem cell) therapies targeted to the endothelium in COPD.